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The overflows of 3,4-dihydroxyphenylalanine, dopamine, noradrenaline, and 3,4-dihydroxyphenylglycol in canine portal vein superfused in vitro were studied before, during, and after depolarization of sympathetic nerve endings. The four compounds were separated from superfusate and from tissue on Sep-Pak C-18 cartridges and quantified by HPLC with electrochemical detection. Physiological and biochemical methods were used to show that the compound released was most probably 3,4-dihydroxyphenylalanine; the identity of the other endogenous compounds has been established previously. Release of 3,4-dihydroxyphenylalanine was calcium and frequency dependent, inhibited by a-m-L-p-tyrosine (an inhibitor of tyrosine hydroxylase) and augmented by 3-hydroxybenzylhydrazine (an inhibitor of aromatic amino acid decarboxylase). The overflows of dopamine, noradrenaline, and 3,4-dihydroxyphenylglycol from the vein were calcium and frequency dependent. It was estimated that under control conditions, approximately 80% of the total 3,4-dihydroxyphenylalanine that was synthesized was directed to catecholamine biosynthesis, approximately 8% overflowed from the vein, and approximately 14% remained unchanged within the tissue. It is concluded that 3,4-dihydroxyphenylalanine and dopamine are released together with noradrenaline and 3,4-dihydroxyphenylglycol from portal vein upon nerve depolarization.

Factors that increase resistance to blood flow through the hepatic sinusoids when portal hypertension occurs in the absence of significant hepatic fibrosis are not completely understood. Experiments were designed to test the hypothesis that endothelin-1 (ET-1) is one of the humoral factors that increases sinusoidal vascular resistance in a bile ductligated noncirrhotic portal hypertensive (BDL) rat. The effect of ET-1 and nitric oxide (NO) on contractility of rings of portal vein taken from BDL rats was tested. The effect of ET-1 and NO on intrahepatic resistance in an isolated perfused liver was studied, and localization of ET-1 in the liver was identified by immunohistochemistry. Portal vein rings in BDL rats showed increased maximal tension in response to ET-1, as well as a shift of the dose-response curve to the left as compared with sham-operated animals. Removal of the endothelium further increased contractility. In isolated perfused liver studies, ET-1 increased portal resistance in both sham operated and BDL rats. Portal hypertension is a circulatory consequence of increased portal blood flow and increased resistance to hepatic sinusoidal blood flow 1 . Nitric oxide (NO) is believed to be a significant factor contributing to increased portal blood flow, 2 but the factors responsible for increasing vascular resistance within the liver are not clearly established, especially in noncirrhotic portal hypertension. A major factor that may increase sinusoidal resistance in cirrhosis is fibrosis with nodule formation, which distorts hepatic sinusoidal architecture, thus increasing resistance to blood flow. Fibrosis, however, is a late feature of liver disease. Thus, early in the onset of portal hypertension, before fibrosis becomes sufficiently established to distort sinusoidal structure, there may be humoral factors that initiate an increase in portal resistance. The role of humoral factors is suggested by recent studies that indicate that portal resistance is decreased by vasodilators such as papavarine and sodium nitroprusside. 3 Endothelin-1 (ET-1) is a member of a family of 21 amino acid peptides, which are potent constrictors of vascular smooth muscle. ET-1 is elevated in the peripheral blood of patients with chronic liver disease with or without ascites [4][5][6] and in the hepatorenal syndrome. 7 ET-1 has been identified in endothelial cells of the hepatic sinusoids, portal vein, and hepatic central vein 8 and has been shown to cause contraction of hepatic sinusoids as well as preterminal portal venules. 9-11 Studies of cirrhotic liver tissue in humans have shown enhanced ET-1 expression, activated hepatic stellate cells (HSC) being the major site of synthesis. 12-13 Endothelin receptors expression is increased in portal hypertensive rats 14 and bosentan, a mixed ET A and ET B receptor antagonist, lowers portal pressure in cirrhotic rats, as well as portal vein stenosed animals. 15 Thus, indirect evidence suggests that ET-1 can act as a paracrine or autocrine factor contributing to increased resistance t...